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In the first of a three-part series on genetic testing, we look at how specific drugs can be used to treat cancers with particular DNA profiles
 A bank executive Pradeep Kumar Bhargava, 62, was diagnosed with advanced colorectal cancer in January, he was asked if he wanted to take a genetic test. He agreed – and found out he was suitable for a type of drug that targeted his specific kind of cancer. It caused less severe side effects, shrank the cancer more significantly and offered a prolonged survival over what chemotherapy alone could give him. Mr Bhargava, a vegetarian who does not smoke and has no family history of colorectal cancer, said: “My wife and I base our decisions on evidence. We decided I should go for the test and wait for the results before starting treatment so as not to waste time and money. I’m glad I was found suitable for the drug.” He has had weekly infusions of the drug since February, on top of fortnightly chemotherapy sessions, and his condition has been improving.
More types of genetic tests that detect specific mutations in cancer cells are being used on cancer patients, which help doctors decide the kind of medication they should have. The first that came along about 10 years ago was a test for a mutation in breast cancer cells. The Diagnostic Molecular Oncology Centre in National University Hospital (NUH), which specialises in genetic testing of cancer, now does almost 20 types of tests. Of these, the more widely used ones include tests for mutations in colorectal, lung and stomach cancer. These tests have emerged in the last three years.
As more of such tests become available, usage has also grown. For example, the number of tests for a lung cancer mutation, called the epidermal growth factor receptor (EGFR) mutation, done in the centre and other laboratories in NUH, jumped from 693 in 2009 to 1,196 last year. The number of tests conducted for a mutation that occurs in breast and stomach cancer rose from 303 in 2009 to 467 last year.
Singapore General Hospital is the other facility here that does these tests. The emergence of such testing is an exciting new frontier for cancer treatment that promises more precise, tailored medicine for the individual. The catch: While the tests cost at most several hundred dollars, the cost of the drugs that target those mutations run into the thousands, putting the drugs out of reach for many people. A person’s genes – made up of deoxyribonucleic acid (DNA) or molecules that contain instructions to cells to develop and function – can mutate spontaneously. Sometimes, this happens because of external factors such as radiation, chemicals and viruses, and can result in cancer.
Genetic tests check for specific genes or mutations in the genes by looking for components of the genes like DNA, or for substances like proteins produced by the genes or mutations. The genetic tests to determine cancer treatment are done on cancer cells and not healthy cells. The mutations found in the cancer cells are not hereditary and cannot be passed down to the next generation, said Dr Tham Chee Kian, an associate consultant at the National Cancer Centre’s department of medical oncology. This group of genetic tests profiles “the enemy”, rather than the patient, said Dr Wong Seng Weng, a medical oncologist at the Singapore Medical Group.
Cancer is usually classified by the type and shape of cells and how far they have spread, but genetic tests allow for even more detailed classification so that treatment can be more precise and effective, said Dr Kong Hwai Loong, a medical oncologist practising at Mount Elizabeth and Novena medical centres. For example, lung cancer has traditionally been split into small cell lung cancer and non-small cell lung cancer. Non-small cell lung cancer, which makes up about 85 per cent of all lung cancer cases, can be further divided into adenocarcinoma, squamous cell carcinoma and large cell carcinoma.
A genetic test can now identify a mutation in the EGFR, a “growth switch” on the surface of lung cells, in people with non-small cell lung cancer and often adenocarcinoma in particular. Patients with this mutation are given one of two targeted drugs, which blocks the mutation from making cancer cells proliferate, with minimal side effects. In Mr Bhargava’s case, the genetic test looks for a mutation in colorectal cancer cells, known as the Kras mutation. Doctors know not to use a particular type of drug in patients with this mutation, as it is rendered useless. The genetic tests for medication are mostly recommended only for those with advanced cancer, because the drugs involved do not improve the cure rates for those with early cancer.
The exception is for a mutation in breast cancer called the Her-2 mutation, for which a targeted drug benefits even patients with early cancer. A test for this mutation is done routinely for all breast cancer patients. In some cases, a more accurate further test is needed. Dr Wong Nan Soon, a senior consultant at the National Cancer Centre Singapore, said: “The Her-2 story is a success story, as it moved from being used in advanced cancer to early cancer too. The drug halves the risk of breast cancer relapse.” For some patients with colorectal cancer, the targeted drug can help to shrink the tumour so effectively that it can be removed by surgery when it previously could not, said Dr Kong. This brings with it the hope of remission, he said.
However, some patients – possibly up to a third, as shown by a United States study – decline to take such genetic tests, often because the drugs are too costly, doctors said. Genetic tests for cancer drugs cost between $170 and $600 each, while a month’s supply of a targeted drug costs about $3,000 to $11,000. Those with diseases for which genetic testing is part of the treatment can use their compulsory medical savings account, Medisave, and national health insurance MediShield to pay for the tests, said the Ministry of Health.
In such cases, the fees of the tests will be subsidised for patients in subsidised wards in public hospitals, it said. But the costs of targeted drugs are not subsidised. Ms Le Thi Minh, 52, a Vietnamese lung cancer patient who was treated here, was given a targeted drug after testing positive for the EGFR mutation a year ago. She said: “I heard cancer treatment comes with a lot of side effects and I was very scared. “The money was worth spending because I feel well now and I’m happy that I can do what I want.”
BREAST AND STOMACH CANCER
TEST: In the last decade, all breast cancer patients have had their cancer cells analysed for a mutation in a type of “growth switch” on their surfaces called Her-2. The mutation causes the cells to produce a large number of growth switches, and the cells proliferate, explained Dr Wong Seng Weng, a medical oncologist at the Singapore Medical Group. A test checks for the level of a protein – which is produced in excess by a cell with the Her-2 mutation – as a proxy for the mutation. In some cases, the result of this test is not clear and a more accurate but expensive test that checks for the mutation itself is done. Since last year, patients with stomach cancer in the fourth stage have also been tested for this mutation. It occurs in about 25 per cent of all breast cancer patients and about 15 per cent of advanced stomach cancer patients.
TREATMENT: Patients with the mutation are given a targeted drug called trastuzumab, sold under the brand Herceptin. Breast cancer patients take this for a year. The drug binds to the Her-2 protein and reduces cell proliferation.
EFFECTS: Studies have shown that about 85 per cent of patients on the drug did not have a relapse within five years, compared to 65 per cent of those who did not take the drug. It shrinks advanced stomach cancer, but not as well as breast cancer.
COST: The test for the protein costs about $170 to $210, while that to check for the mutation costs $330 to $580. The drug costs about $3,000 to $5,000 a month.
LUNG CANCER
TEST: In the last couple of years, patients with lung cancer in the fourth stage have been tested for a mutation in the epidermal growth factor receptor (EGFR). The test extracts and analyses deoxyribonucleic acid (DNA) from the lung cancer cells. The EGFR is a “growth switch” on the surface of lung cells, said Dr Wong Seng Weng, a medical oncologist at the Singapore Medical Group. Normally, this switch is turned on only after the command centre of the cell sends a protein messenger to tell the cell to multiply, he explained. The mutation jams the growth switch in the “on” mode, so the cell keeps growing, he said. The mutation is common in Asian women who do not smoke, for reasons unknown. It occurs in 60 to 70 per cent of cases in this group.
TREATMENT: Patients who have the mutation are given one of two targeted drugs on its own or with chemotherapy: gefitinib, sold under the brand Iressa; and erlotinib, sold under the brand Tarceva. The drugs get into the cell, bind to the malfunctioning growth switch from inside and block the growth signals from reaching it. This eventually kills the cell.
EFFECTS: They shrink the tumour significantly – by more than half – in about 70 to 80 per cent of patients who were on them, compared to about 40 per cent of patients who had only chemotherapy. They also prolong the survival period. About 15 years ago, before the drugs were available, the average survival period for patients with such cancer was about four to six months. Better chemotherapy and targeted drugs have lengthened this to one to two years now.
COST: The test costs about $250 to $500, and a month’s supply of a targeted drug costs about $4,000 to $5,000.
COLORECTAL CANCER
TEST: For two to three years now, deoxyribonucleic acid (DNA) has been extracted from the cancer cells of patients with colorectal cancer in the fourth stage, and tested for the Kras mutation. The Kras protein is a messenger that relays growth signals between the command centre of the colorectal cell and a growth switch on the surface of the cell. When it mutates, it continuously sends signals to the command centre to order growth, even without getting any signals from the growth switch. The growth switch normally sends these signals after receiving external growth signals. The Kras protein mutation occurs in about half of colorectal cancer patients.
TREATMENT: Patients who do not have the mutation will be given a targeted drug called cetuximab, sold under the brand Erbitux, either on its own or with chemotherapy. This drug binds to the growth switch, blocking it from receiving external growth signals. But a mutated Kras protein will continue to emit growth signals on its own, so patients with it are unsuitable for the drug.
EFFECTS: Studies have shown that 59 per cent of patients on cetuximab had their tumours shrunk by more than half, compared to 43 per cent who were on chemotherapy alone. Patients on cetuximab and chemotherapy can now live an average of two years, up from a year with only chemotherapy in the 1990s, figures from the United States show. Targeted drugs have also shrunk some previously inoperable tumours to make them operable, said Dr Kong Hwai Loong, a medical oncologist who practises at Mount Elizabeth and Novena medical centres. This has raised the proportion of advanced colorectal patients who can have surgery from 2 to 8 per cent, improving their chances of remission, he said.
COST: The test costs about $225 to $500, while a month’s treatment with cetuximab costs about $10,000 to $11,000.
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